Two lines of defense against pathogens are the innate immune system and the adaptive immune system. The innate immune system targets features common to many different pathogens but misses those pathogens lacking these features. The adaptive immune system is both more specific and wide-reaching. To respond effectively to a vast array of pathogens, this type of immune system must be tremendously flexible. The adaptive immune system follows the principles of evolution: an enormously diverse set of potentially useful proteins is generated; these proteins are then subjected to intense selection so that only cells that express useful proteins flourish and continue development, until an effective immune response to a specific invader is generated.

34.1 Antibodies Possess Distinct Antigen-Binding and Effector Units

The major immunoglobulin in the serum is immunoglobulin G. An IgG protein is a heterotetramer with two heavy chains and two light chains. Treatment of IgG molecules with proteases such as papain produces three fragments: two F_ab fragments that retain antigen-binding activity and an F_c fragment that retains the ability to activate effector functions such as the initiation of the complement cascade. The F_ab fragments include the L chain and the amino-terminal half of the H chain; the F_c domain is a dimer consisting of the carboxyl-terminal halves of two H chains. Five different classes of antibody—IgG, IgM, IgA, IgD, and IgE—differ in their heavy chains and, hence, in their effector functions.

34.2 Antibodies Bind Specific Molecules Through Hypervariable Loops

One particular protein fold is found in many of the key proteins of the immune system. The immunoglobulin fold consists of a pair of β sheets that pack against each other, linked by a single disulfide bond. Loops projecting from one end of the structure form a binding surface that can be varied by changing the amino acid sequences within the loops. Domains with immunoglobulin folds are linked to form antibodies and other classes of proteins in the immune system, including T-cell receptors. Two chains come together to form the binding surface of an antibody. Three loops from each domain, the complementarity-determining regions, form an essentially continuous surface that can vary tremendously in shape, charge, and other characteristics to allow particular antibodies to bind to molecules ranging from small molecules to large protein surfaces.

34.3 Diversity Is Generated by Gene Rearrangements

The tremendous diversity of the amino acid sequences of antibodies is generated by segmental rearrangements of genes. For antibody κ light chains, 1 of 40 variable regions is linked to 1 of 5 joining regions. The combined VJ unit is then linked to the constant region. Thousands of different genes can be generated in this manner. Similar arrays are rearranged to form the genes for the heavy chains, but an additional region called the diversity region lies between the V and the J regions. The combination of L and H chains, each obtained through such rearranged genes, can produce more than 10⁸ distinct antibodies. Different classes of antibodies are also generated by gene rearrangements that lead to class switching. Oligomerization of membrane-bound antibody molecules initiates a signal-transduction cascade inside B cells. Key steps in this signaling process include the phosphorylation of specific tyrosine residues in sequences termed immunoreceptor tyrosine-based activation motifs, present in proteins that associate with the membrane-bound antibodies.

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34.4 Major-Histocompatibility-Complex Proteins Present Peptide Antigens on Cell Surfaces for Recognition by T-Cell Receptors

Intracellular pathogens such as viruses and mycobacteria cannot be easily detected. Intracellular proteins are constantly being cut into small peptides by proteasomes and displayed in class I major-histocompatibility-complex proteins on cell surfaces. Such peptides lie in a groove defined by two helices in the class I MHC proteins. The combination of MHC protein and peptide can be bound by an appropriate T-cell receptor. T-cell receptors resemble the antigen-binding domains of antibodies in structure, and diversity in T-cell-receptor sequence is generated by V(D)J gene rearrangements. The T-cell receptor recognizes features of both the peptide and the MHC molecule that presents it.

Cytotoxic T cells initiate apoptosis in cells to which they bind through interactions between T-cell receptors and class I MHC–peptide complexes aided by interactions with the coreceptor molecule CD8. Helper T cells recognize peptides presented in class II MHC proteins, a distinct type of MHC protein expressed only on antigen-presenting cells, such as B cells and macrophages. Helper T cells express the coreceptor CD4 rather than CD8. CD4 interacts with class II MHC proteins present on antigen-presenting cells. Signaling pathways, analogous to those in B cells, are initiated by interactions between MHC–peptide complexes and T-cell receptors and the CD8 and CD4 coreceptors. Human immunodeficiency virus damages the immune system by infecting and killing cells that express CD4, such as helper T cells.

34.5 The Immune System Contributes to the Prevention and the Development of Human Diseases

In principle, the immune system is capable of generating antibodies and T-cell receptors that bind to self-molecules—that is, molecules that are normally present in a healthy and uninfected individual organism. Selection mechanisms prevent such self-directed molecules from being expressed at high levels. The selection process includes both positive selection, to enrich the population of cells that express molecules that have the potential to bind foreign antigens in an appropriate context, and negative selection, which eliminates cells that express molecules with too high an affinity for self-antigens. Autoimmune diseases such as insulin-dependent diabetes mellitus can result from the amplification of a response against a self-antigen. Vaccines stimulate immunological memory so as to prevent, and even eradicate, disease.